Combination therapy for cardiovascular diseases

Abstract

Provided herein are methods of treating or reducing the risk of a cardiovascular disease using a lipid lowering agent (e.g., statin and/or PCSK9 inhibitor) and an anti-inflammatory agent (e.g., a pro-inflammatory cytokine inhibitor). Further provided herein are methods of predicting the recurrence rate of a subject who has received or is undergoing therapy for a cardiovascular disease with a lipid lowering agent on the basis of the C-reactive protein (CRP) level in the subject. In some embodiments, the recurrence rate can be reduced using an anti-inflammatory agent.

What is claimed is: 
     
         1 . A method of treating a cardiovascular disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a lipid lowering agent and an anti-inflammatory agent. 
     
     
         2 . The method of  claim 1 , wherein the anti-inflammatory agent is a proinflammatory cytokine inhibitor. 
     
     
         3 . The method of  claim 1  or  claim 2 , wherein the anti-inflammatory agent comprises an IL-1 inhibitor, an IL-1 receptor (IL-1R) inhibitor, an IL-6 inhibitor, an IL-6 receptor (IL-6R) inhibitor, a NLRP3 inhibitor, a TNF inhibitor, an IL-8 inhibitor, an IL-18 inhibitor, an inhibitor of natural killer cells, or combinations thereof. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the anti-inflammatory agent is a nucleic acid, an aptamer, an antibody or antibody fragment, an inhibitory peptide, or a small molecule. 
     
     
         5 . The method of  claim 3  or  claim 4 , wherein the anti-inflammatory agent comprises an IL-1 inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the IL-1 inhibitor is an IL-1α inhibitor. 
     
     
         7 . The method of  claim 6 , wherein the IL-1α inhibitor is an anti-sense oligonucleotide against IL-1α, MABp1, or sIL-1RI. 
     
     
         8 . The method of  claim 5 , wherein the IL-1 inhibitor is an IL-1β inhibitor. 
     
     
         9 . The method of  claim 8 , wherein the IL-1β inhibitor is an anti-sense oligonucleotide against IL-1β, canakinumab, gevokizumab, diacerein, LY2189102, CYT013, sIL-1RII, VX-740, or VX-765. 
     
     
         10 . The method of  claim 5 , wherein the IL-1 inhibitor is suramin sodium, methotrexate-methyl-d3, methotrexate-methyl-d3 dimethyl ester, or diacerein. 
     
     
         11 . The method of claim any one of  claims 3 - 10 , wherein the anti-inflammatory agent comprises an IL-1R inhibitor. 
     
     
         12 . The method of  claim 11 , wherein the IL-1R inhibitor is an IL-1R antagonist. 
     
     
         13 . The method of claim A 11  or claim A 12 , wherein the IL-1R inhibitor is an anti-sense oligonucleotide against IL-1R, anakinra, Rilonacept, MEDI-8968, sIL-1RI, EBI-005, interleukin-1 receptor antagonist (IL-1RA), or AMG108. 
     
     
         14 . The method of any one of  claims 3 - 13 , wherein the anti-inflammatory agent comprises an IL-6 inhibitor. 
     
     
         15 . The method of  claim 14 , wherein the IL-6 inhibitor is an anti-sense oligonucleotide against IL-6, siltuximab, sirukumab, clazakizumab, olokizumab, elsilimomab, IG61, BE-8, CNTO328 PGE1 and its derivatives, PGI2 and its derivatives, or cyclophosphamide. 
     
     
         16 . The method of any one of  claims 3 - 15 , wherein the anti-inflammatory agent comprises an IL-6R inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the IL-6R inhibitor is an IL-6R antagonist. 
     
     
         18 . The method of  claim 16  or  claim 17 , wherein the IL-6R inhibitor is an anti-sense oligonucleotide against IL-6R, tocilizumab, sarilumab, PM1, AUK12-20, AUK64-7, AUK146-15, MRA, or AB-227-NA. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the anti-inflammatory agent comprises a NLRP3 inhibitor. 
     
     
         20 . The method of  claim 19 , wherein the NLPR3 inhibitors is an anti-sense oligonucleotide against NLPR3, colchicine, MCC950, CY-09, ketone metabolite beta-hydroxubutyrate (BHB), a type I interferon, resveratrol, arglabin, CB2R, Glybenclamide, Isoliquiritigenin, Z-VAD-FMK, or microRNA-223. 
     
     
         21 . The method of any one of  claims 3 - 20 , wherein the anti-inflammatory agent comprises a TNF inhibitor. 
     
     
         22 . The method of  claim 21 , wherein the TNF inhibitor is an anti-sense oligonucleotide against TNF, infliximab, adalimumab, certolizumab pegol, golimumab, etanercept (Enbrel), thalidomide, lenalidomide, pomalidomide, a xanthine derivative, bupropion, 5-HT2A agonist, or a hallucinogen. 
     
     
         23 . The method of any one of  claims 3 - 22 , wherein the anti-inflammatory agent comprises an IL-8 inhibitor. 
     
     
         24 . The method of  claim 23 , wherein the IL-8 inhibitor is an anti-sense oligonucleotide against IL8, HuMab-10F8, Reparixin, Curcumin, Antileukinate, Macrolide, or a trifluoroacetate salt. 
     
     
         25 . The method of any one of  claims 3 - 24 , wherein the anti-inflammatory agent comprises an IL-18 inhibitor. 
     
     
         26 . The method of  claim 25 , wherein the IL-18 inhibitor is an anti-sense oligonucleotide against IL-18, IL-18 binding protein, IL-18 antibody, NSC201631, NSC61610, or NSC80734. 
     
     
         27 . The method of any one of  claims 3 - 26 , wherein the anti-inflammatory agent comprises an inhibitor of natural killer cells. 
     
     
         28 . The method of  claim 27 , wherein the inhibitor of natural killer cells is an antibody targeting natural killer cells. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the anti-inflammatory agent comprises methotrexate. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein the anti-inflammatory agent comprises arhalofenate. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein the lipid lowering agent comprises a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. 
     
     
         32 . The method of any one of  claims 1 - 30 , wherein the PCSK9 inhibitor is a natural PCSK9 inhibitor, a PCSK9 antibody, an antisense nucleic acid, a peptide inhibitor, a PCSK9 vaccine, or a small molecule inhibitor. 
     
     
         33 . The method of  claim 32 , wherein the natural PCSK9 inhibitor is berberine, annexin A2, or adnectin. 
     
     
         34 . The method of  claim 32 , wherein the small molecule inhibitor is PF-06446846, anacetrapib, or K-312. 
     
     
         35 . The method of  claim 32 , wherein the PCSK9 antibody is alirocumab, evolocumab, 1D05-IgG2, RG-7652, LY3015014, or bococizumab. 
     
     
         36 . The method of  claim 32 , wherein the antisense nucleic acid is an RNAi molecule. 
     
     
         37 . The method of  claim 36 , wherein the RNAi molecule is inclisiran or ALN-PCS. 
     
     
         38 . The method of  claim 32 , wherein the peptide inhibitor is a peptide that mimics an EGFa domain of low-density lipoprotein receptor (LDL-R). 
     
     
         39 . The method of  claim 32 , wherein the PCSK9 vaccine comprises an antigenic PCSK9 peptide. 
     
     
         40 . The method of any one of  claims 1 - 39 , wherein the lipid lowering agent comprises a HMG-CoA reductase inhibitor. 
     
     
         41 . The method of  claim 40 , wherein the HMG-CoA reductase inhibitor is a statin. 
     
     
         42 . The method of  claim 41 , wherein the statin is simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, or pitivastatin. 
     
     
         43 . The method of any one of  claims 1 - 42 , wherein the lipid lowering agent is a fibric acid derivative (fibrate), a bile acid sequestrant, a resin, a nicotinic acid agent, a cholesterol absorption inhibitor, acyl-coenzyme A, a cholesterol acyl transferase (ACAT) inhibitor, a cholesteryl ester transfer protein (CETP) inhibitor, a LDL receptor antagonist, a farnesoid X receptor (FXR) antagonist, a sterol regulatory binding protein cleavage activating protein (SCAP) activator, a microsomal triglyceride transfer protein (MTP) inhibitor, a squalene synthase inhibitor, or a peroxisome proliferation activated receptor (PPAR) agonist. 
     
     
         44 . The method of any one of  claims 1 - 43 , wherein the lipid lowering agent and the anti-inflammatory agent are administered together. 
     
     
         45 . The method of any one of  claims 1 - 43 , wherein the lipid lowering agent and the anti-inflammatory agent are administered separately. 
     
     
         46 . The method of any one of  claims 1 - 45 , wherein the lipid lowering agent and/or the anti-inflammatory agent is administered intranasally, intravenously, intramuscularly, subcutaneously, or orally. 
     
     
         47 . The method of any one  claims 1 - 46 , wherein the level or activity of a proinflammatory cytokine in the subject is reduced. 
     
     
         48 . The method of any one of  claims 1 - 47 , wherein the level or activity of C-reactive protein (CRP) in the subject is reduced. 
     
     
         49 . The method of any one of  claims 1 - 48 , wherein the level or activity of non-high-density lipoprotein (HDL)-cholesterol in the subject is reduced. 
     
     
         50 . The method of any one of  claims 1 - 49 , wherein the level or activity of LDL-cholesterol in the subject is reduced. 
     
     
         51 . The method of any one of  claims 1 - 50 , wherein the level or activity of total cholesterol in the subject is reduced. 
     
     
         52 . The method of any one of  claims 1 - 51 , wherein the level or activity of apolipoprotein B (ApoB) in the subject is reduced. 
     
     
         53 . The method of any one of  claims 1 - 52 , wherein the level or activity of triglycerides in the subject is reduced. 
     
     
         54 . The method of any one of  claims 1 - 53 , wherein the ratio of total cholesterol to HDL-cholesterol in the subject is reduced. 
     
     
         55 . The method of any one of  claims 1 - 54 , wherein the occurrence of non-fatal myocardial infarction is reduced. 
     
     
         56 . The method of any one of  claims 1 - 54 , wherein the occurrence of non-fatal stroke is reduced. 
     
     
         57 . The method of any one of  claims 1 - 54 , wherein the rate of cardiovascular mortality is reduced. 
     
     
         58 . The method of any one of  claims 1 - 57 , wherein the cardiovascular disease is myocardial infarction, stroke, acute coronary syndrome, myocardial ischemia, chronic stable angina pectoris, unstable angina pectoris, cardiovascular death, coronary re-stenosis, coronary stent re-stenosis, coronary stent re-thrombosis, recurrent cardiovascular events, revascularization, angioplasty, transient ischemic attack, pulmonary embolism, vascular occlusion, or venous thrombosis. 
     
     
         59 . A method of reducing a recurrence rate of a cardiovascular disease in a subject who has received or is undergoing therapy with a lipid lowering agent, the method comprising administering to the subject an effective amount of an anti-inflammatory agent. 
     
     
         60 . A method of predicting a recurrence rate of a cardiovascular disease in a subject who has received or is undergoing therapy with the lipid lowering agent, the method comprising measuring a level of C-reactive protein (CRP) in the subject and determining that the subject is likely to have recurrence of the cardiovascular disease if the CRP level is above a pre-determined value. 
     
     
         61 . The method of  claim 60 , wherein the pre-determined value is 3 mg/L. 
     
     
         62 . The method of  claim 60 , wherein the pre-determined value is 2 mg/L. 
     
     
         63 . The method of  claim 60 , wherein the pre-determined value is 1 mg/L. 
     
     
         64 . A method of treating a cardiovascular disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody comprising a first antigen-binding domain that binds a proinflammatory cytokine and a second antigen-binding domain that binds a proprotein convertase subtilisin/kexin type 9 (PCSK9). 
     
     
         65 . The method of  claim 64 , wherein the proinflammatory cytokine is IL-1, IL-1 receptor (IL-1R), IL-6, IL-6 receptor (IL-6R), NLRP3, TNF, IL-8, or IL-18. 
     
     
         66 . The method of  claim 65 , wherein the first antigen-binding domain binds to IL-1. 
     
     
         67 . The method of  claim 66 , wherein the first antigen-binding domain binds to IL-1α. 
     
     
         68 . The method of  claim 66 , wherein the first antigen-binding domain is derived from MABp1. 
     
     
         69 . The method of  claim 66 , wherein the first antigen-binding domain binds to IL-1β. 
     
     
         70 . The method of  claim 69 , wherein the first antigen-binding domain is derived from canakinumab, diacerein, gevokizumab, or LY2189102. 
     
     
         71 . The method of  claim 65 , wherein the first antigen-binding domain binds to IL-1R. 
     
     
         72 . The method of  claim 71 , wherein the first antigen-binding domain is derived from MEDI-8968 or AMG108. 
     
     
         73 . The method of  claim 65 , wherein the first antigen-binding domain binds to IL-6. 
     
     
         74 . The method of  claim 73 , wherein the first antigen-binding domain is derived from siltuximab, sirukumab, clazakizumab, olokizumab, or elsilimomab. 
     
     
         75 . The method of  claim 65 , wherein the first antigen-binding domain binds to IL-6R. 
     
     
         76 . The method of  claim 75 , wherein the first antigen-binding domain is derived from tocilizumab, sarilumab, PM1, AUK12-20, AUK64-7, AUK146-15, or AB-227-NA. 
     
     
         77 . The method of  claim 65 , wherein the first antigen-binding domain binds to NLRP3. 
     
     
         78 . The method of  claim 77 , wherein the first antigen-binding domain is derived from an anti-NLRP3 antibody. 
     
     
         79 . The method of  claim 65 , wherein the first antigen-binding domain binds to TNF. 
     
     
         80 . The method of  claim 79 , wherein the first antigen-binding domain is derived from infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept (Enbrel). 
     
     
         81 . The method of  claim 65 , wherein the first antigen-binding domain binds to IL-8. 
     
     
         82 . The method of  claim 81 , wherein the first antigen-binding domain is derived from HuMab-10F8. 
     
     
         83 . The method of  claim 65 , wherein the first antigen-binding domain binds to IL-18. 
     
     
         84 . The method of  claim 83 , wherein the first antigen-binding domain is derived from an IL-18 antibody. 
     
     
         85 . The method of any one of  claims 64 - 84 , wherein the second antigen-binding domain is derived from alirocumab, evolocumab, 1D05-IgG2, RG-7652, LY3015014, or bococizumab. 
     
     
         86 . The method of any one of  claims 64 - 85 , wherein the bispecific antibody comprises a common Fc region. 
     
     
         87 . The method of any one of  claims 64 - 86 , wherein the bispecific antibody is a monoclonal bispecific antibody. 
     
     
         88 . The method of any one of  claims 64 - 87 , further comprising administering to the subject a therapeutically effective amount of a HMG-CoA reductase inhibitor. 
     
     
         89 . The method of  claim 88 , wherein the HMG-CoA reductase inhibitor is a statin. 
     
     
         90 . The method of  claim 89 , wherein the statin is simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, or pitivastatin. 
     
     
         91 . The method of any one of  claims 64 - 89 , wherein the bispecific antibody is administered intravenously, intramuscularly, subcutaneously, or orally. 
     
     
         92 . The method of any one  claims 64 - 91 , wherein the level or activity of a proinflammatory cytokine in the subject is reduced. 
     
     
         93 . The method of any one of  claims 64 - 92 , wherein the level or activity of C-reactive protein (CRP) in the subject is reduced. 
     
     
         94 . The method of any one of  claims 64 - 93 , wherein the level or activity of non-high-density lipoprotein (HDL)-cholesterol in the subject is reduced. 
     
     
         95 . The method of any one of  claims 64 - 94 , wherein the level or activity of LDL-cholesterol in the subject is reduced. 
     
     
         96 . The method of any one of  claims 64 - 95 , wherein the level or activity of total cholesterol in the subject is reduced. 
     
     
         97 . The method of any one of  claims 64 - 96 , wherein the level or activity of apolipoprotein B (ApoB) in the subject is reduced. 
     
     
         98 . The method of any one of  claims 64 - 97 , wherein the level or activity of triglycerides in the subject is reduced. 
     
     
         99 . The method of any one of  claims 64 - 98 , wherein the ratio of total cholesterol to HDL-cholesterol in the subject is reduced. 
     
     
         100 . The method of any one of  claims 64 - 99 , wherein the occurrence of non-fatal myocardial infarction is reduced. 
     
     
         101 . The method of any one of  claims 64 - 99 , wherein the occurrence of non-fatal stroke is reduced. 
     
     
         102 . The method of any one of  claims 64 - 101 , wherein the rate of cardiovascular mortality is reduced. 
     
     
         103 . A method of treating a cardiovascular disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody comprising a first antigen-binding domain that binds IL-1 and a second antigen-binding domain that binds a proprotein convertase subtilisin/kexin type 9 (PCSK9). 
     
     
         104 . The method of  claim 103 , wherein the first antigen-binding domain binds to IL-1α. 
     
     
         105 . The method of  claim 104 , wherein the first antigen-binding domain is derived from MABp1. 
     
     
         106 . The method of  claim 103 , wherein the first antigen-binding domain binds to IL-1β. 
     
     
         107 . The method of  claim 106 , wherein the first antigen-binding domain is derived from canakinumab, diacerein, gevokizumab, or LY2189102. 
     
     
         108 . The method of any one of  claims 103 - 107 , wherein the second antigen-binding domain is derived from alirocumab, evolocumab, 1D05-IgG2, RG-7652, LY3015014, or bococizumab.